Gilteritinib hemifumarate

Alias: ASP2215 hemifumarate; ASP-2215 hemifumarate; ASP 2215 hemifumarate; Gilteritinib hemifumarate; Trade name: Xospata

Cat No.:V3135 Purity: ≥98%

COA Product Data Instructions for use SDS

Gilteritinib hemifumarate Chemical Structure CAS No.: 1254053-84-3
Product category: FLT3

This product is for research use only, not for human use. We do not sell to patients.

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Other Forms of Gilteritinib hemifumarate:

Gilteritinib(ASP2215)

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Top Publications Citing lnvivochem Products

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J Am Chem Soc 2022,144:21831-21836.

Cell 2020,183:1202-1218.e25.

Science Adv 2022:8,eabm9427.

Nature 2021,597(7874):119-125.

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Product Description
Bioactivity & Protocols
Physicochemical Properties
Solubility Data
Calculators
Biological Data

Product Description

Gilteritinib hemifumarate (ASP2215; ASP-2215 hemifumarate; Xospata), the hemifumarate salt of Gilteritinib (ASP2215), is a marketed anti-AML drug acting as a dual inhibitor of FLT3/AXL with IC50 values of 0.29 nM and 0.73 nM for FLT3 and AXL respectively. The US FDA approved gelderitinib in November 2018 for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML). With an IC50 roughly 800-fold higher than that needed to inhibit c-KIT (230 nM), it potently inhibits FLT3. Treatment options for leukemia like AML with FLT3-ITD and FLT3-D835 mutations include gelderitinib. With an IC50 value of 0.29 nM for FLT3, gelderitinib is approximately 800-fold more potent than c-KIT and inhibits FLT3, leukocyte tyrosine kinase (LTK), anaplastic lymphoma kinase (ALK), and AXL kinases by over 50% in vitro among the 78 tyrosine kinases tested.

Biological Activity I Assay Protocols (From Reference)

Targets

FLT3 (IC50 = 0.29 nM); LTK (IC50 = 0.35 nM); AXL (IC50 = 0.73 nM); EML4-ALK (IC50 = 1.2 nM); c-KIT (IC50 = 230 nM)

ln Vitro

Gilteritinib (ASP2215), out of the 78 tyrosine kinases examined, inhibits the kinases FLT3, leukocyte tyrosine kinase (LTK), anaplastic lymphoma kinase (ALK), and AXL by more than 50% at 1 nM. For FLT3, the IC50 value is 0.29 nM, which makes it about 800-fold more potent than c-KIT[1]. Gilteritinib, at concentrations of either 1 nM (FLT3, LTK, ALK, and AXL) or 5 nM (TRKA, ROS, RET, and MER), inhibits the activity of eight of the 78 tested kinases by more than 50%. For FLT3, the IC50 is 0.29 nM, and for AXL, it is 0.73 nM. At an IC50 that is roughly 800-fold more potent than that needed to inhibit c-KIT (230 nM), gelderitinib inhibits FLT3. Gilteritinib's antiproliferative efficacy is assessed in relation to MV4-11 and MOLM-13 cells, which are endogenously FLT3-ITD-expressing. Gilteritinib inhibits the growth of MOLM-13 and MV4-11 cells after five days of treatment, with mean IC50s of 2.9 nM (95% CI: 1.4-5.8 nM) and 0.92 nM (95% CI: 0.23-3.6 nM), respectively. MV4-11 cell growth suppression is correlated with inhibition of FLT3 phosphorylation. Following two hours of treatment with 0.1 nM, 1 nM, and 10 nM Gilteritinib, respectively, the phosphorylated FLT3 levels are 57%, 8%, and 1% higher than those of the vehicle control cells. Furthermore, the suppression of phosphorylated ERK, STAT5, and AKT—all downstream targets of FLT3 activation—occurs at concentrations as low as 0.1 nM or 1 nM. Gilteritinib is administered to MV4-11 cells that expressed exogenous AXL in order to study its effects on AXL inhibition. Gilteritinib treatment reduces phosphorylated AXL levels by 38%, 29%, and 22% at concentrations of 1 nM, 10 nM, and 100 nM for 4 hours[2].

ln Vivo

After administering oral Gilteritinib at a dose of 10 mg/kg for four days, the concentration of the drug in tumors in MV4-11 xenografted mice was found to be over 20 times higher than that in plasma. MV4-11 tumor growth is dose-dependently inhibited during a 28-day treatment with gelderitinib, and at doses greater than 6 mg/kg, total tumor regression is induced. Furthermore, gerteritinib prolongs the survival of mice receiving intravenous MV4-11 cell transplants and reduces the tumor burden in the bone marrow[1].

Enzyme Assay

TK-ELISA or off-chip mobility shift assays are used to test the kinase inhibitory activity of Gilteritinib against a panel of 78 tested kinases, with ATP concentrations roughly equivalent to each kinase's Km value. Initially, the inhibitory effect of each compound on TK activity is evaluated at two concentrations of Gilteritinib (1 nM and 5 nM). Next, additional research employing a range of Gilteritinib doses is carried out to ascertain IC50 values for c-KIT and kinases whose activity is inhibited by more than half at 1 nM Gilteritinib. FLT3, LTK, AXL, and c-KIT IC50 studies are carried out using TK-ELISA and MSA assays; the HTRF KinEASE-TK assay is used to determine the IC50 value of echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK)[2].

Cell Assay

The CellTiter-Glo Luminescent Cell Viability Assay is used to evaluate the impact of gelderitinib on MV4-11 and MOLM-13 cells. Further research is done to investigate the impact of quizartinib and gilteritinib on Ba/F3 cells that express FLT3-ITD, FLT3-D835Y, FLT3-ITD-D835Y, FLT3-ITD-F691 L, or FLT3-ITD-F691I. For five days, DMSO or increasing concentrations of Gilteritinib (0.01, 0.1, 1, 10, and 100 nM) are applied to MV4-11 and MOLM-13 cells. CellTiter-Glo is used to measure the viability of the cells[2].

Animal Protocol

Mice: In nude mice transplanted with MV4-11 AML cells, antitumor activity is assessed. Additionally, the pharmacokinetics in xenografted mice are examined. Gilteritinib (10 mg/kg) is given orally to MV4-11 xenografted mice for a period of four days as part of their treatment. Gilteritinib treatment for 28 days causes total tumor regression at doses greater than 6 mg/kg and dose-dependent inhibition of MV4-11 tumor growth[1].

References

[1]. ASP2215, a novel FLT3/AXL inhibitor: Preclinical evaluation in acute myeloid leukemia (AML). 2014 ASCO Annual Meeting.

[2]. Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia. Invest New Drugs. 2017 Oct;35(5):556-565.

These protocols are for reference only. InvivoChem does not independently validate these methods.

Physicochemical Properties

Molecular Formula	C29H44N8O3₀.₅C₄H₄O₄
Molecular Weight	610.75
Elemental Analysis	C, 60.96; H, 7.59; N, 18.35; O, 13.10
CAS #	1254053-84-3
Related CAS #	Gilteritinib;1254053-43-4
Appearance	Solid powder
SMILES	CCC1=C(N=C(C(=N1)C(=O)N)NC2=CC(=C(C=C2)N3CCC(CC3)N4CCN(CC4)C)OC)NC5CCOCC5.CCC1=C(N=C(C(=N1)C(=O)N)NC2=CC(=C(C=C2)N3CCC(CC3)N4CCN(CC4)C)OC)NC5CCOCC5.C(=C/C(=O)O)\C(=O)O
InChi Key	UJOUWHLYTQFUCU-WXXKFALUSA-N
InChi Code	InChI=1S/2C29H44N8O3.C4H4O4/c21-4-23-28(31-20-9-17-40-18-10-20)34-29(26(33-23)27(30)38)32-21-5-6-24(25(19-21)39-3)37-11-7-22(8-12-37)36-15-13-35(2)14-16-36;5-3(6)1-2-4(7)8/h25-6,19-20,22H,4,7-18H2,1-3H3,(H2,30,38)(H2,31,32,34);1-2H,(H,5,6)(H,7,8)/b;;2-1+
Chemical Name	(E)-but-2-enedioic acid;6-ethyl-3-[3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]anilino]-5-(oxan-4-ylamino)pyrazine-2-carboxamide
Synonyms	ASP2215 hemifumarate; ASP-2215 hemifumarate; ASP 2215 hemifumarate; Gilteritinib hemifumarate; Trade name: Xospata
HS Tariff Code	2934.99.9001
Storage	Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility Data

Solubility (In Vitro)

DMSO: ~2 mg/mL

Water: N/A

Ethanol: N/A

Solubility (In Vivo)

Solubility in Formulation 1: 10 mg/mL (16.37 mM) in 50% PEG300 +50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

(Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.6373 mL	8.1867 mL	16.3733 mL
	5 mM	0.3275 mL	1.6373 mL	3.2747 mL
	10 mM	0.1637 mL	0.8187 mL	1.6373 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)

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Calculation results

Working concentration： mg/mL；

Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.

Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH₂O，mix and clarify.

Note： (1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.

Biological Data

Gilteritinib inhibits cell growth in AML cells and blocks phosphorylation of FLT3 and its downstream targets.Invest New Drugs.2017 Oct;35(5):556-565.
Antitumor activity of gilteritinib in an MV4–11 xenograft AML mouse model.Invest New Drugs.2017 Oct;35(5):556-565.
Gilteritinib significantly decreases leukemic burden and increases survival in an intra-bone marrow transplantation model of AML.Invest New Drugs.2017 Oct;35(5):556-565.
Computational modeling of gilteritinib binding to wild-type FLT3.Invest New Drugs.2017 Oct;35(5):556-565.
Gilteritinib induces regression of FLT3 mutant-expressing tumors in a mouse xenograft model.Invest New Drugs.2017 Oct;35(5):556-565.
Antitumor Effect of Gilteritinib in Combination with Azacitidine in Mice Xenografted with MV4-11 Cells.Blood. 2016, 128:2830.